Our overall aim is to elucidate the mechanisms that underlie L-dopa-induced dyskinesias (LIDs) and to develop anti-dyskinetic strategies, with a focus on the nicotinic cholinergic system. L-dopa therapy is the gold standard for Parkinson's disease treatment. However, its use is associated with movement abnormalities, such as dyskinesias that may be as debilitating as the disease itself. Few treatments are available for LIDs, possibly because the mechanisms responsible for their development are still uncertain. Although extensive studies have implicated numerous neurotransmitters, the cholinergic system has received little attention to date. This is somewhat surprising given the overlapping network of dopaminergic terminals and cholinergic interneurons in the striatum, and the well-known ability of nicotinic receptors to regulate striatal dopamine release. With this in mind, we hypothesized that the nicotinic cholinergic system plays a role in LIDs, and initiated experiments in which nicotine and L-dopa were administered to parkinsonian monkeys. Our preliminary data demonstrate that nicotine consistently reduced peak and total LIDs (~50%) in parkinsonian monkeys. In addition, a crossover study subsequently showed that nicotine treatment also reduced LIDs in monkeys that had previously been given L-dopa. There was no decline in the antiparkinsonian action of L-dopa. We plan to extend these novel behavioral findings, as well as investigate the mechanisms responsible for the nicotine-induced reduction of LIDs through the following specific aims. First, we will identify the nicotine-dosing regimen that most effectively reduces LIDs. To approach this, we will test the effect of nicotine given at the same time and also after L-dopa administration, and determine the dose and time dependency of the nicotine-induced decline in LIDs. Second, we will identify the nicotinic receptor subtypes associated with the nicotine-induced decrease in dyskinesias. This work will provide a basis for the studies in Aim 3 to test the effect of nAChR subtype agonists for their antidyskinetic properties. Lastly, we will study the molecular and cellular mechanisms by which nicotine reduces dyskinesias. Treatment with nicotine, or select nicotinic agonists, represents a novel approach to reduce dyskinesias and could lead to the development of new strategies to attenuate this debilitating complication of L-dopa treatment in patients with Parkinson's disease. PUBLIC HEALTH RELEVANCE Our data show that nicotine administration reduces L-dopa induced dyskinesias in parkinsonian monkeys. The objective of this proposal is to evaluate the optimal mode of administration, to determine the nicotinic receptor subtypes and to understand the mechanisms through which nicotine exerts its antidyskinetic action. These studies have the potential to open up a new research direction for the treatment of dyskinesias in Parkinson's disease using drugs targeted to the nicotinic cholinergic system.